title: CD8+ dendritic cell-mediated tolerance of autoreactive CD4+ T cells is deficient in NOD mice and can be corrected by blocking CD40L.
abstract: DCs are important mediators of peripheral tolerance for the prevention of autoimmunity. Chimeric αDEC-205 antibodies with attached antigens allow in vivo antigen-specific stimulation of T cells by CD8(+) DCs, resulting in tolerance in nonautoimmune mice. However, it is not clear whether DC-mediated tolerance induction occurs in the context of ongoing autoimmunity. We assessed the role of CD8(+) DCs in stimulation of autoreactive CD4(+) T cells in the NOD mouse model of type 1 diabetes. Targeting of antigen to CD8(+) DCs via αDEC-205 led to proliferation and expansion of β-cell specific BDC2.5 T cells. These T cells also produced IL-2 and IFN-γ and did not up-regulate FoxP3, consistent with an activated rather than tolerant phenotype. Similarly, endogenous BDC peptide-reactive T cells, identified with I-A(g7) tetramers, did not become tolerant after antigen delivery via αDEC-205: no deletion or Treg induction was observed. We observed that CD8(+) DCs from NOD mice expressed higher surface levels of CD40 than CD8(+) DCs from C57BL/6 mice. Blockade of CD40-CD40L interactions reduced the number of BDC2.5 T cells remaining in mice, 10 days after antigen targeting to CD8 DCs, and blocked IFN-γ production by BDC2.5 T cells. These data indicate that the ability of autoreactive CD4(+) T cells to undergo tolerance mediated by CD8(+) DCs is defective in NOD mice and that blocking CD40-CD40L interactions can restore tolerance induction.
authors.affiliation: 1.Diabetes, Endocrinology, and Obesity Branch, NIDDK, NIH, Bldg. 10, CRC, West Labs, 5-5940, Bethesda, MD 20892, USA. tarbellk@niddk.nih.gov.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Price
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Beauchamp
authors.forename: Gwendoline
authors.initials: G
authors.lastname: Rahir
authors.forename: Yongge
authors.initials: Y
authors.lastname: Zhao
authors.forename: Cosima C
authors.initials: CC
authors.lastname: Rieger
authors.forename: Annie W
authors.initials: AW
authors.lastname: Lau-Kilby
authors.forename: Kristin V
authors.initials: KV
authors.lastname: Tarbell
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000941:Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D010455:Peptides / Q000276:immunology; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D000906:Antibodies; D000941:Antigens; D019013:CD40 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D008024:Ligands; D010455:Peptides; D051193:Toll-Like Receptors; D023201:CD40 Ligand; D007371:Interferon-gamma
keywords: CD40; DEC-205; peripheral tolerance; type 1 diabetes